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系統識別號 U0026-1507201412375700
論文名稱(中文) 以晶片檢測陽性液態培養及抗酸性染色陽性痰液檢體中結核桿菌群對第一線及第二線藥物之抗藥性
論文名稱(英文) Detection of first- and second-line drug resistance of Mycobacterium tuberculosis complex in positive liquid cultures and acid-fast stain positive sputum samples by an array
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 102
學期 2
出版年 103
研究生(中文) 蔡瑜函
研究生(英文) Yu-Han Tsai
學號 t36014068
學位類別 碩士
語文別 中文
論文頁數 246頁
口試委員 指導教授-張長泉
口試委員-柯文謙
口試委員-盧柏樑
口試委員-周如文
中文關鍵字 結核桿菌群  抗藥性結核菌  寡核苷酸晶片 
英文關鍵字 Array  Oligonucleotide probe  Mycobacterium tuberculosis complex  Drug resistance  Mycobacteria Growth Indicator Tube (MGIT) 
學科別分類
中文摘要 結核病是由結核桿菌群(Mycobacterium tuberculosis complex)感染所引起,為世界三大傳染病之一。全世界結核病發生率雖有下降的趨勢,但是抗藥性結核菌卻有增加的趨勢。結核桿菌群的藥物感受性試驗需三週,因此需要一個更快速的方法。本研究利用先前設計的晶片,評估其用於檢測陽性液態培養及抗酸性染色陽性痰液檢體中結核桿菌群對一線 [rifampin (RIF), isoniazid (INH), ethambutol (EMB)]及二線藥物[streptomycin (SM), ofloxacin (OFX), kanamycin (KA), capreomycin (CAP)及amikacin (AM)] 的抗藥性。利用13對引子進行多重聚合酶鏈反應,接著將產物和晶片進行雜合反應。自胸腔病院(衛生福利部),收集1426個陽性液態培養檢體(731位病人),其中553支(207位病人)檢體培養出結核桿菌群,以晶片檢測其中結核桿菌群的靈敏度及特異性分別為100%及98.9%。晶片檢測抗藥性(以病人為計算基礎)的靈敏度分別為91.7% (RIF), 88.9% (INH), 100% (EMB), 82.4% (SM), 100% (OFX), 100% (KA), 50.0% (CAP)及100% (AM);特異性分別為98.9% (RIF), 99.4% (INH), 99.5% (EMB), 100% (SM), 100% (OFX), 100% (KA), 99.0% (CAP)及99.5% (AM);陽性預測值分別為91.7% (RIF), 97.0% (INH), 92.9% (EMB), 100% (SM), 100% (OFX), 100% (KA), 33.3% (CAP)及66.7% (AM);陰性預測值分別為98.7% (RIF), 97.7% (INH), 100% (EMB), 98.4% (SM), 100% (OFX), 100% (KA), 99.5% (CAP)及100% (AM)。檢測多重抗藥結核菌及廣泛抗藥結核菌的靈敏度分別為84.2%及100%,而特異性分別為99.5%及100%。以晶片直接檢測抗酸性染色陽性痰液檢體的效果不佳。除了CAP以外,本晶片能在一個工作天有效檢測陽性液態培養中結核桿菌群對於重要的一線及二線抗結核藥物之抗藥性。
英文摘要 Tuberculosis (TB) is caused by Mycobacterium tuberculosis complex (MTBC). The global incidence of TB is decreasing, while drug-resistant TB cases are increasing. The conventional method for drug susceptibility testing of MTBC takes 3 weeks. This study aimed to detect point mutations in the genes of MTBC conferring resistance to the first line [rifampin (RIF), isoniazid (INH), ethambutol (EMB)] and second line drugs [streptomycin (SM), ofloxacin (OFX), kanamycin (KM), capreomycin (CAP), and amikacin (AM)] in positive Mycobacteria Growth Indicator Tube (MGIT) cultures and acid-fast stain positive sputum samples. The method consisted of multiplex PCR (13 pairs of primers) amplification of the relevant genes, followed by hybridization of the amplicons to probes on the array. Of the 1426 positive MGIT cultures analyzed, 553 cultures (from 207 patients) were found to contain MTBC. The sensitivity and specificity of the array for detecting MTBC in positive MGIT cultures were 100% and 98.9%, respectively. Good performance was found for the array to detect drug resistance of RIF, EMB, OFX, KM and AM, and moderate performance was obtained for INH and SM, while poor performance was obtained for CAP. In addition, the performance of the array for direct detection of drug resistance of MTBC in sputum samples was not acceptable.

Key words: Array, Oligonucleotide probe, Mycobacterium tuberculosis complex, Drug resistance, Mycobacteria Growth Indicator Tube (MGIT)

INTRODUCTION
In 2013 WHO report, an estimated 450,000 people developed MDR-TB. XDR-TB had been reported by 92 countries. The average proportion of MDR-TB cases with XDR-TB is 9.6%. The conventional drug susceptibility testing of MTBC takes about 3 weeks. Drug resistance of MTBC is associated with point mutations in several genes, including rpoB for RIF, katG and promoter of inhA for INH, embB for EMB, rpsL and rrs for SM, gyrA and gyrB for OFX, rrs and the promoter of eis for second-line injectable drugs (KM, CAP and AM). The aim of this study was to detect point mutations of these genes in positive MGIT cultures and acid-fast stain positive sputum samples by an array. The results were compared with those of the proportional method.

MATERIALS AND METHODS
A total of 1426 positive MGIT cultures and 200 acid-fast stain positive sputum samples were obtained from Chest Hospital, Ministry of Health and Welfare. One milliliter of each MGIT sample was used for DNA extraction followed by PCR. Thirteen pairs of primers were used to amplify rpoB, katG, the inhA promoter, embB, rpsL, rrs, gyrA, gyrB, the promoter of eis and the internal trascribed spacer region by multiplex PCR. Each primer was labeled with a digoxigenin molecule at its 5’ end. Oligonucleotide probes were spotted on positively charged nylon membrane and amplicons were hybridized with probes on the array. After hybridization, alkaline phosphatase-conjugated anti-digoxigenin antibodies were used to produce the hybridization signals.

RESULTS AND DISCUSSION
The sensitivities of the array (based on patient number) were 91.7% (RIF), 88.9% (INH), 100% (EMB), 82.4% (SM), 100% (OFX), 100% (KM), 50% (CAP), and 100% (AM), respectively, while the specificities were respectively 98.9% (RIF), 99.4% (INH), 99.5% (EMB), 100% (SM), 100% (OFX), 100% (KM), 99% (CAP), and 99.5% (AM). The array had good performance for detecting drug resistance of RIF, EMB, OFX, KM and AM, however moderate performance was obtained for INH and SM, and poor performance was obtained for CAP. For detection of MDR-TB and XDR-TB, the sensitivities were 84.2% and 100%, respectively, while the specificities were respectively 99.5% and 100%. The array was not feasible for direct detection of drug resistance of MTBC in sputum samples.

CONCLUSION
The array can be used to detect gene mutations causing drug resistance to some important first and second line anti-TB antibiotics in positive MGIT cultures, except CAP, in a working day.
論文目次 中文摘要 I
Extended Abstract III
致謝 VII
目錄 VIII
表目錄 XII
圖目錄 XIV
緒論 1
結核桿菌群(Mycobacterium tuberculosis complex, MTBC) 1
結核病之流行病學 1
臨床實驗室診斷 4
結核菌抗藥性之分子機轉 5
1. Rifampin (RIF) 5
2. Isoniazid (INH) 6
3. Ethambutol (EMB) 7
4. Streptomycin (SM) 8
5. Fluoroquinolones (FQs) 9
6. Kanamycin (KM), Capreomycin (CAP)及Amikacin (AM) 9
結核菌抗藥性之分子檢測方法 10
研究目的 12
研究架構 12
材料與方法 14
陽性MGIT檢體之收集 14
抗酸性染色陽性痰液檢體之收集 15
陽性MGIT檢體之DNA萃取 15
抗酸性染色陽性痰液檢體之DNA萃取 16
晶片之製備 17
多重聚合酶鏈反應(multiplex PCR) 19
晶片雜合反應(array hybridization) 19
晶片雜合反應結果之判讀 21
抗藥性基因定序 21
GenoType® MTBDRplus套組 22
Sensititre® MYCOTB plates套組 24
靈敏度(sensitivity)、特異性(specificity)、陽性預測值(positive predictive value, PPV)、陰性預測值(negative predictive value, NPV)、及一致性(agreement)之定義 25
晶片偵測結核桿菌群抗藥性之評估(以病人為計算基礎) 27
晶片偵測極限(detection limit)之決定 28
結果 29
陽性MGIT檢體中結核桿菌群之檢測 29
抗酸性染色陽性痰液檢體中結核桿菌群之檢測 29
陽性MGIT檢體中結核桿菌群抗藥性之檢測及不一致檢體之基因定序 30
一、RIF之抗藥性檢測及基因定序 30
二、INH之抗藥性檢測及基因定序 31
三、EMB之抗藥性檢測及基因定序 32
四、SM之抗藥性檢測及基因定序 33
五、OFX之抗藥性檢測及基因定序 34
六、KM之抗藥性檢測及基因定序 34
七、CAP之抗藥性檢測及基因定序 34
八、AM之抗藥性檢測及基因定序 35
九、MDR-TB及XDR-TB之檢測 36
十、晶片結果評估(以病人為計算基礎) 36
抗酸性染色陽性痰液檢體中結核桿菌群之抗藥性檢測 37
偽陽性菌株之最低抑菌濃度(MIC)試驗 37
晶片之偵測極限(detection limit) 38
討論 39
晶片鑑定結核桿菌群之能力 39
以晶片檢測含MTBC及NTM混合培養之陽性MGIT檢體中MTBC之抗藥性 40
RIF抗藥性和rpoB基因突變之相關性 40
INH抗藥性和katG及inhA上游基因突變之相關性 42
EMB抗藥性和embB基因突變之相關性 44
SM之抗藥性和rrs及rpsL基因突變之相關性 45
OFX抗藥性和gyrA及gyrB基因突變之相關性 45
KM、CAP、AM抗藥性和rrs及eis上游區域基因突變之相關性 46
其他突變對晶片雜合反應之影響 47
晶片對結核桿菌群異質抗藥性(hetero-resistance)之檢測 47
抗藥性晶片與商業化套組之比較 48
結論 50
參考文獻 51
附錄 138
附錄一、結核病治療 138
附錄二、MGIT檢體總表 140
附錄三、痰液檢體總表 226
附錄四、菌株之抗藥相關基因定序 237
附錄五、混合培養之MGIT檢體之病人其他檢體之培養結果 240
附錄六、統計更新 244
附錄七、晶片檢測痰液檢體中結核桿菌群之表現(去除24支抗酸性染色為scanty檢體) 245
附錄八、晶片偵測極限(detection limit) 246
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